Human Gene Module / Chromosome 2 / KIF5C

KIF5CKinesin family member 5C

Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
3 / 8
Rare Variants / Common Variants
12 / 0
Aliases
KIF5C, FLJ44735,  KIAA0531,  KINN,  MGC111478,  NKHC,  NKHC-2,  NKHC2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
2q23.1-q23.2
Associated Disorders
ASD, EP, EPS
Relevance to Autism

A de novo missense variant in the KIF5C gene that was predicted to be damaging was identified in an autistic proband (Awadalla et al., 2010). Inherited missense variants in this gene that were predicted to be damaging were identified in Chinese ASD probands in Li et al., 2017. Phenotypic characterization of four previously published cases (from de Ligt et al., 2013, Poirier et al., 2013, Januar et al., 2014, and Cavallin et al., 2016) and two novel cases in Michels et al., 2017 implicated KIF5C missense variants as the cause of a neurodevelopmental disorder characterized by infantile-onset epilepsy, absent speech, malformations of cortical development, and, in three cases, stereotypic hand movements.

Molecular Function

Neuron-specific kinesin heavy chain (kinesin is a microtubule-associated force-producing protein that may play a role in organelle transport)

Reports related to KIF5C (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Direct measure of the de novo mutation rate in autism and schizophrenia cohorts. Awadalla P , et al. (2010) Yes -
2 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
3 Support Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Poirier K , et al. (2013) No Epilepsy/seizures
4 Support Somatic mutations in cerebral cortical malformations. Jamuar SS , et al. (2014) No Pachygyria
5 Support Recurrent KIF5C mutation leading to frontal pachygyria without microcephaly. Cavallin M , et al. (2015) No Absent speech, stereotypic hand movements, pachygy
6 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
7 Recent Recommendation Mutations of KIF5C cause a neurodevelopmental disorder of infantile-onset epilepsy, absent language, and distinctive malformations of cortical deve... Michels S , et al. (2017) No Absent speech, stereotypic hand movements
8 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
C>T R802C, R872C missense_variant De novo NA - 20797689 Awadalla P , et al. (2010)
c.513G>T p.Cys172Phe missense_variant Unknown - - 25140959 Jamuar SS , et al. (2014)
c.2439G>T p.Gly814Val missense_variant Unknown - - 23033978 de Ligt J , et al. (2012)
c.1783C>T p.Asp595= missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.420G>A p.Arg141Gln missense_variant De novo NA - 23033978 de Ligt J , et al. (2012)
c.420G>A p.Arg141Gln missense_variant De novo NA - 29048727 Michels S , et al. (2017)
c.1918G>A p.Ser640= missense_variant De novo NA - 31452935 Feliciano P et al. (2019)
c.420G>A p.Arg141Gln missense_variant De novo NA - 26384676 Cavallin M , et al. (2015)
c.1344A>G p.Glu449Gly missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2385C>T p.Ala796Val missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2541G>A p.Arg848Lys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.710A>T p.Glu237Val missense_variant De novo (germline mosaicism) - Multiplex 23603762 Poirier K , et al. (2013)
Common Variants  

No common variants reported.

SFARI Gene score
3S

Suggestive Evidence, Syndromic

A de novo missense variant in the KIF5C gene that was predicted to be damaging was identified in an autistic proband (Awadalla et al., 2010). Inherited missense variants in this gene that were predicted to be damaging were identified in Chinese ASD probands in Li et al., 2017. Phenotypic characterization of four previously published cases (from de Ligt et al., 2013, Poirier et al., 2013, Januar et al., 2014, and Cavallin et al., 2016) and two novel cases in Michels et al., 2017 implicated KIF5C missense variants as the cause of a neurodevelopmental disorder characterized by infantile-onset epilepsy, absent speech, malformations of cortical development, and, in three cases, stereotypic hand movements.

Score Delta: Score remained at 4S

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo missense variant in the KIF5C gene that was predicted to be damaging was identified in an autistic proband (Awadalla et al., 2010). Inherited missense variants in this gene that were predicted to be damaging were identified in Chinese ASD probands in Li et al., 2017. Phenotypic characterization of four previously published cases (from de Ligt et al., 2013, Poirier et al., 2013, Januar et al., 2014, and Cavallin et al., 2016) and two novel cases in Michels et al., 2017 implicated KIF5C missense variants as the cause of a neurodevelopmental disorder characterized by infantile-onset epilepsy, absent speech, malformations of cortical development, and, in three cases, stereotypic hand movements.

4/1/2018
icon
4.4 + S

Increased from to 4.4 + S

Description

4S

Krishnan Probability Score

Score 0.61320097232496

Ranking 146/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99951559715187

Ranking 932/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.94145518732924

Ranking 14939/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 2

Ranking 393/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.42920690030661

Ranking 1130/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
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